Deaths due to opioid overdose have reached epidemic levels and are a recognized health crisis.  Full mOR agonists such as morphine, heroin, codeine, fentanyl and oxycodone are recognized as important medications to treat pain, but their abuse leads to tolerance, dependence and death by respiratory suppression. A screen of a virtual library yielded potent and selective mOR ligands typified by the previously disclosed compound, PZM21. In this report, we discuss the use of urea and phenol isosteres to optimize the CNS permeability of the PZM21 scaffold. Our efforts led to a novel series of carbamate derivatives typified by RM201006 (mOR cAMP EC<sub>50</sub> (%Effic.) = 35 nM (80%) with significantly improved CNS permeability in rat (brain/plasma ratio = 3.2) and mouse (brain/plasma ratio = 4.1).<br/>

Optimization of novel mOR ligands for enhanced CNS penetration

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.